Myotonic Dystrophy Research Articles

Excessive daytime sleepiness in myotonic dystrophy: a narrative review.

Excessive daytime sleepiness (EDS) is a common and debilitating symptom in both forms of myotonic dystrophy (DM), significantly impacting patients' quality of life. The review focuses on the purpose of examining the current understanding of EDS in these conditions, the difficulty in correctly accessing it, the recent findings related to its etiology and prevalence, and a summary of potential therapeutic implications. We conducted a comprehensive search through PubMed, selecting studies that provided significant insights into the mechanisms, prevalence, and management of EDS in DM1 and DM2. EDS is highly prevalent in both DM1 and DM2. Polysomnographic studies have revealed prominent dysregulation of REM sleep in DM1, suggesting a possible narcoleptic-like phenotype and alterations in NREM sleep that contributes to daytime sleepiness. Other factors have been proposed to explain EDS in DM1, including dysregulation of the sleep-wake circadian rhythm through nocturnal actigraphy analysis. The central origin of EDS is increasingly delineated supported by serotonin and orexin pathways dysfunction, and recent neuroradiological findings showing that in DM1 hippocampus volume was positively correlated with self-reported fatigue and somnolence. Sleep-disordered breathing and respiratory dysfunctions are prevalent in DM, their direct correlation with EDS remains complex and inconclusive, but respiratory evaluation should be recommended if obstructive sleep apneas or respiratory muscle dysfunctions are suspected. Drug interventions, such as modafinil and mexiletine, have shown promise in managing excessive daytime sleepiness and reducing myotonia without significant cardiac conduction effects. Enhancing EDS management in myotonic dystrophy is key to improving overall patient well-being.

Prevalence of cardiovascular implantable electronic devices in children with type 1 myotonic dystrophy.

Type 1 myotonic dystrophy (DM1) is a neuromuscular disorder of multiple organ systems with important electrophysiologic (EP) manifestations, leading to a cumulative incidence of sudden death of 6.6%. Due to genetic anticipation, there is a pediatric subset of this patient population. However, most EP research on DM1 patients has been in adults, making cardiac care for pediatric patients difficult and directed by adult guidelines which often leads to cardiovascular implantable electronic device (CIED) implants. We sought to investigate the prevalence of CIEDs in the pediatric DM1 population. The Vizient® Clinical Data Base was queried from October 2019 to October 2023 for admissions with and without ICD-10 code for myotonic dystrophy (G71.11), with and without codes for presence of a pacemaker or ICD (Z95.0, Z95.810). Patients who were identified were stratified by age: Pediatric (0-21 years) and Adult (22-50 years). Prevalence of CIED in pediatric DM1 was 2.1% and in adult DM1 was 15.8%. When comparing to pediatric and adult patients with CIED and without DM1, the odds ratio for CIED in pediatric DM1 was 48.8, compared to 23.3 for CIED in adult DM1. There are pediatric DM1 patients who have received CIED despite a lack of data to inform this decision-making. Further research will be important to ensure appropriate use of CIED in this population and to develop appropriate guidelines to direct management.

From bedside to genetic analysis: New insights into pathophysiology of melanoma, basal cell carcinoma, and other cancers

AbstractObjectivePatients with myotonic muscular dystrophy (MMD) were observed to have numerous basal cell carcinoma (BCC) and abnormal dysplastic nevi (DN) on non‐sun exposed skin. Simultaneously a large study published in the Journal of American Medical Association (JAMA) illustrated that patients with MMD have “overall” an increased risk for cancer development. Based on these findings, this author in 2010 postulated that dysregulation of RNA binding proteins (RBP), responsible for clinical manifestations of MMD, is also responsible for the development of BCC and melanoma.MethodsTo report new research elucidating the etiology of melanoma, BCC, MMD‐induced cancers, and potentially other environmentally induced malignancies.ResultsDysregulation of RBP induces aberrant mRNA splicing; recent data indicates that abnormal mRNA splicing not just plays a key role in the pathogenesis of melanoma but is a hallmark of essentially all human malignancies.ConclusionThe author's hypothesis is that ultraviolet (UV) radiation induces DNA damage in intronic regions of a variety of genes. Furthermore, these UV‐induced abnormal DNA dimers, repeats and mutations interfere with normal mRNA splicing thus producing abnormal proteins. These abnormal proteins in turn activate oncogenic pathways such as hedgehog, MAP kinase, and WNT.

Effects of interrupting residues on DNA dumbbell structures formed by CCTG tetranucleotide repeats associated with myotonic dystrophy type 2.

Myotonic dystrophy type 2 (DM2) is a neurogenerative disease caused by caprylic/capric triglyceride (CCTG) tetranucleotiderepeat expansions in intron 1 of the cellular nucleic acid-binding protein (CNBP) gene. Non-B DNA structures formed by CCTG repeats can promote genetic instability, whereas interrupting motifs of NCTG (N = A/T/G) within CCTG repeats help to maintain genomic stability. However, whether the interrupting motifs can affect DNA structures of CCTG repeats remains unclear. Here, we report that four CCTG repeats with an interrupting 3'-A/T/G residue formed dumbbell structures, whereas a non-interrupting 3'-C residue resulted in a multi-loop structure exhibiting conformational dynamics that may contribute to a higher tendency of escaping from DNA mismatch repair and causing repeat expansions. The results provide new structural insights into the genetic instability of CCTG repeats in DM2.

NMR structures of small molecules bound to a model of an RNA CUG repeat expansion.

Trinucleotide repeat expansions fold into long, stable hairpins and cause a variety of incurable RNA gain-of-function diseases such as Huntington's disease, the myotonic dystrophies, and spinocerebellar ataxias. One approach for treating these diseases is to bind small molecules to the structured RNAs. Both Huntington's disease-like 2 (HDL2) and myotonic dystrophy type 1 (DM1) are caused by a r(CUG) repeat expansion, or r(CUG)exp. The RNA folds into a hairpin structure with a periodic array of 1×1 nucleotide UU loops (5'CUG/3'GUC; where the underlined nucleotides indicate the Us in the internal loop) that sequester various RNA-binding proteins (RBP) and hence the source of its gain-of-function. Here, we report NMR-refined structures of single 5'CUG/3'GUC motifs in complex with three different small molecules, a di-guandinobenzoate (1), a derivative of 1 where the guanidino groups have been exchanged for imidazole (2), and a quinoline with improved drug-like properties (3). These structures were determined using nuclear magnetic resonance (NMR) spectroscopy and simulated annealing with restrained molecular dynamics (MD). Compounds 1, 2, and 3 formed stacking and hydrogen bonding interactions with the 5'CUG/3'GUC motif. Compound 3 also formed van der Waals interactions with the internal loop. The global structure of each RNA-small molecule complexes retains an A-form conformation, while the internal loops are still dynamic but to a lesser extent compared to the unbound form. These results aid our understanding of ligand-RNA interactions and enable structure-based design of small molecules with improved binding affinity for and biological activity against r(CUG)exp. As the first ever reported structures of RNA r(CUG) repeats bound to ligands, these structures can enable virtual screening campaigns combined with machine learning assisted de novo design.

Periodic limb movements during sleep in children with neuromuscular disease or cerebral palsy – An important potential contributor to sleep-related morbidity

ObjectivesPoor sleep is frequently reported in children with neuromuscular diseases (NMD) and cerebral palsy (CP) however breathing disorders during sleep are often the clinical focus. Periodic limb movements (PLMs) have an increased prevalence in adults with NMD and may contribute to sleep disturbance in this population. We assessed the prevalence of PLMs in children with NMD or CP. MethodsRetrospective review of polysomnography (PSG) with leg electromyography in children age 1–18 years with NMD (including Duchenne muscular dystrophy, myotonic dystrophy, spinal muscular atrophy) or CP performed at a paediatric sleep centre 2004–2022. ResultsLeg electromyography was available in at least 1 PSG in 239 children (125 NMD, 114 CP), and in 2 PSGs in 105 children (73 NMD, 32 CP). At initial PSG, 72 (30 %) were female with a median age 9y and respiratory disturbance index 3.5/h (interquartile range 1.3–9.9/h). Elevated PLM index (PLMI; >5/h) occurred in 9.6 % of each of the CP and NMD groups, quantified by initial PSG. Overall, PLMI increased from baseline (median 0, maximum 33/h) to follow-up (median 0, maximum 55.8/h; p < 0.05). In those with an elevated PLMI, arousal percentage attributable to PLMs was up to 25 % (median 7.5 %). ConclusionsElevated PLMI occurred at a higher prevalence in children with NMD and CP than reported in other clinic-referred paediatric populations. It is important that PLMs are not overlooked as identification and treatment may help improve sleep outcomes. Further research is required to understand the pathophysiology and consequences of PLMs specifically in this population.

Mouse models of non-dystrophic and dystrophic myotonia exhibit nociplastic pain-like behaviors.

Pain is a prominent and debilitating symptom in myotonic disorders, yet its physiological mechanisms remain poorly understood. This study assessed preclinical pain-like behavior in murine models of pharmacologically induced myotonia and myotonic dystrophy type 1 (DM1). In both myotonia congenita and DM1, impairment of the CLCN1 gene, which encodes skeletal muscle voltage-gated CLC-1 chloride channels, reduces chloride ion conductance in skeletal muscle cells, leading to prolonged muscle excitability and delayed relaxation after contraction. We used the CLC-1 antagonist anthracene-9-carboxylic acid (9-AC) at intraperitoneal doses of 30 or 60 mg/kg and HSA LR20b DM1 mice to model CLC-1-induced myotonia. Our experimental approach included in vivo pain behavioral testing, ex vivo calcium imaging, and whole-cell current-clamp electrophysiology in mouse dorsal root ganglion (DRG) neurons. A single injection of 9-AC induced myotonia in mice, which persisted for several hours and resulted in long-lasting allodynic pain-like behavior. Similarly, HSA LR20b mice exhibited both allodynia and hyperalgesia. Despite these pain-like behaviors, DRG neurons did not show signs of hyperexcitability in either myotonic model. These findings suggest that myotonia induces nociplastic pain-like behavior in preclinical rodents, likely through central sensitization mechanisms rather than peripheral sensitization. This study provides insights into the pathophysiology of pain in myotonic disorders and highlights the potential of using myotonic mouse models to explore pain mechanisms and assess novel analgesics. Future research should focus on the central mechanisms involved in myotonia-induced pain and develop targeted therapies to alleviate this significant clinical burden.

Greater cortical thinning and microstructural integrity loss in myotonic dystrophy type 1 compared to myotonic dystrophy type 2

BackgroundMyotonic dystrophy is a multisystem disorder characterized by widespread organic involvement including central nervous system symptoms. Although myotonic dystrophy disease types 1 (DM1) and 2 (DM2) cover a similar spectrum of symptoms, more pronounced clinical and brain alterations have been described in DM1. Here, we investigated brain volumetric and white matter alterations in both disease types and compared to healthy controls (HC).MethodsMRI scans were obtained from 29 DM1, 27 DM2, and 56 HC. We assessed macro- and microstructural brain changes by surface-based analysis of cortical thickness of anatomical images and tract-based spatial statistics of fractional anisotropy (FA) obtained by diffusion-weighted imaging, respectively. Global MRI measures were related to clinical and neuropsychological scores to evaluate their clinical relevance.ResultsCortical thickness was reduced in both patient groups compared to HC, showing similar patterns of regional distribution in DM1 and DM2 (occipital, temporal, frontal) but more pronounced cortical thinning for DM1. Similarly, FA values showed a widespread decrease in DM1 and DM2 compared to HC. Interestingly, FA was significantly lower in DM1 compared to DM2 within most parts of the brain.ConclusionComparisons between DM1 and DM2 indicate a more pronounced cortical thinning of grey matter and a widespread reduction in microstructural integrity of white matter in DM1. Future studies are required to unravel the underlying and separating mechanisms for the disease courses of the two types and their neuropsychological symptoms.

Recurrent pulmonary embolism complicated with myotonic dystrophy type 1

Recurrent pulmonary embolism complicated with myotonic dystrophy type 1

Gastrointestinal involvement in neuromuscular disorders.

Although not often discussed, many of the neuromuscular disorders (NMDs) affect the gastrointestinal tract (GIT). Depending on the type of NMD, the prevalence of GIT involvement ranges from <5% (e.g. hereditary neuropathies, myofibrillar myopathies) to 100% (e.g. MNGIE, OPMD). Particularly in NMDs with multisystem affection, involvement of the GIT can dominate the clinical presentation or at least make up a significant part of the clinical picture. The most prominent representatives of NMDs with multisystem involvement are the mitochondrial disorders (MIDs) and the myotonic dystrophies. The best known syndromic MIDs with GIT involvement are MNGIE, MELAS, Leigh, and Pearson syndromes. Among neuropathies, GIT involvement is most commonly found in ALS and GBS. GIT involvement may also be a feature of myasthenia. The clinical manifestations of GIT involvement are diverse and can affect the entire GIT, from the teeth to the rectum, including the liver and pancreas. The most well-known clinical manifestations of GIT involvement are dysphagia, nausea, vomiting, reflux, hollow organ dysmotility, hepatopathy, diabetes, diarrhea, constipation, and fecal incontinence. Even if treatment can usually only be symptomatic, the therapeutic options are diverse, are often effective, and can significantly and beneficially influence the course of the underlying NMD.

Clarification on "Myotonic Dystrophy Type 1 - An Atypical Presentation".

Clarification on "Myotonic Dystrophy Type 1 - An Atypical Presentation".

Safety and efficacy of immune checkpoint inhibitors (ICI) in patients (pts) with pre-existing neurologic autoimmune diseases (NAID) and Parkinson's disease.

2653 Background: Patients with pre-existing NAID often flare with ICIs; neurological (neuro) immune related adverse events (irAEs) are often morbid or fatal, and little is known about safety of ICI in pts with NAID and other neuro conditions (e.g. Parkinson’s). Thus, we aimed to determine their safety and efficacy in these contexts. Methods: We retrospectively analyzed 71 pts from 5 institutions receiving ICIs with NAIDs and Parkinson’s disease. NAIDs included multiple sclerosis (MS), myasthenia gravis (MG), inflammatory neuropathy, transverse myelitis, Lambert-Eaton, myotonic dystrophy, and multifocal motor neuropathy. We collected demographics, cancer outcomes, NAID characteristics, and safety outcomes. We used descriptive statistics to analyze treatment outcomes, NAID flares, and irAEs. Results: We collected 71 pts, 40 with NAID and 31 with Parkinson’s. 24 had melanoma, 12 non-small cell lung cancer (NSCLC), 3 small cell lung cancer (SCLC), 6 urothelial/bladder, 4 renal cell carcinoma, and 22 other; 60 had metastatic and 11 had localized disease. Median age at ICI start was 72 years (61% male, 39% female); 8 received combination ICI and 63 received monotherapy. Of 40 pts with NAID, 30% had either NAID flares or neurologic irAEs and 33% experienced other (non-neuro) irAEs (Table). Toxicities were particularly severe in MG; 70% (n=7) had MG flare/neuro irAE, 3 of which were fatal. In addition, 31 had Parkinson’s; of these, 12.9% (n=4) had Parkinson’s flares, 3% (n=1) had neuro-irAEs, and 42% (n=13) had other irAEs. One pt died of grade 5 myocarditis/myositis following combination ICI (Table). 5 MS patients responded to therapy (23%), but none were those with NAID flare/neuro irAE. Both MG patients who had non-neuro irAEs responded to treatment. Conclusions: In this cohort of ICI treated pts with prior neuro disorders, we demonstrated that MG pts have high rates of MG flare/neuro irAEs, hospitalizations, and fatalities, but low response rates. In contrast, other NAID (particularly MS) as well as Parkinson’s appeared to have modest risks of flares/neuro irAEs. Notably, Parkinson’s pts had high rates of non-neuro irAEs and response rates. [Table: see text]

EE255 Costs and Healthcare Resource Utilization Evaluation in Myotonic Dystrophy Type 1: Results from the Real-World Care-DM1 Study

EE255 Costs and Healthcare Resource Utilization Evaluation in Myotonic Dystrophy Type 1: Results from the Real-World Care-DM1 Study

Cardiac manifestations in myotonic dystrophy type 1

Aim. To characterize cardiac damage in myotonic dystrophy type 1 (MD1), which is the most common form of hereditary primary muscular pathology in adults.Material and methods. Forty-eight patients with MD1 (31 men, 17 women, mean age 39,2±9,3 years) underwent clinical examination, neuropsychological examination, lipid profile assessment, electrocardiography (ECG), Holter ECG monitoring, and echocar-diography. Four clinical cases are presented that demonstrate clear cardiac manifestations of MD1.Results. The patients did not complain of arrhythmias or chest pain, while 7 (14,6%) had complaints of exercise shortness of breath. Cardiac conduction disorders occurred in 18 (37,5%) patients, which were represented by firstand second-degree atrioventricular (AV) block, his bundle and intraventricular conduction disturbances. According to Holter monitoring, heart rate &lt;60 bpm was recorded in 46 (95,8%) patients, of which 2 (4,2%) were &lt;30 bpm. One (2.1%) patient had atrial fibrillation. According to echocardiography, ventricular enlargement was detected in 3 (6,3%) patients, and atrial enlargement — in 8 (16,7%). None of the patients had an ejection fraction &lt;50%.Conclusion. Cardiac involvement is a common manifestation of MD1. Full cardiac examination can help not only improve the quality of life of patients, but also avoid possible side effects of the prescribed treatment.

Cognitive and emotional disturbances in adult patients with myotonic dystrophy type 1

Cognitive and emotional disturbances in adult patients with myotonic dystrophy type 1

Diagnoses of muscular dystrophy in a veterans health system.

Early diagnosis of a chronic neuromuscular disease such as muscular dystrophy (MD) generally excludes an individual from active-duty military service. However, it is not known whether veterans are sometimes diagnosed with milder forms of MD at a later timepoint. We aimed to determine the prevalence of MD in a veterans health system. We abstracted clinical and genetic test data on patients who received care for a diagnosis of MD at the North Florida/South Georgia Veterans Health System between 2008 and 2021. We then determined which of these individuals would meet criteria for a definite diagnosis of MD, based on electrodiagnostic testing, muscle biopsy, and genetic testing of the individual or an affected first degree relative. We identified 12 patients with definite MD and 36 with possible or probable MD. The definite cases included myotonic dystrophy type 1 (4), myotonic dystrophy type 2 (3), oculopharyngeal MD (2), Becker MD (1), distal MD (1), and facioscapulohumeral MD (1). At least five of the cases classified as definite developed symptoms after discharge from active duty. Clinicians who care for veterans should be knowledgeable about, and have access to, diagnostic testing and treatment options for MD. When conducting MD surveillance, it is important to include veterans health systems as a data source. Mild cases of MD and those of later onset appear to be compatible in some cases with successful completion of military service.

Maternal cell contamination in postnatal umbilical cord blood samples implies a low risk for genetic misdiagnoses.

Maternal cell contamination (MCC) poses a risk for misdiagnosis in prenatal genetic testing, and is examined in accredited diagnostic laboratories However, the awareness of possible MCC in perinatal/postnatal genetic testing, mainly of umbilical cord blood (CB), is lower. We investigated the rate of MCC in DNA from both umbilical CB samples and umbilical cord samples that were sent to our diagnostic laboratory for diagnostic testing between 1995 and 2021 (n=236). MCC was detected in 4% of umbilical CB samples, and in one umbilical cord sample. Particularly tests enriching for a specific variant are very sensitive for low amounts of MCC, as we emphasize here with a false positive diagnosis of myotonic dystrophy type 1 in a newborn. Overall, with appropriate collection and use, umbilical CB and umbilical cord samples are suitable for genetic testing based on the low rates of MCC and misdiagnosis. These findings do however underline the importance of routine MCC testing in umbilical CB samples and umbilical cord samples for both requesting clinicians and diagnostic genetic laboratories.

CaMKIIβ deregulation contributes to neuromuscular junction destabilization in Myotonic Dystrophy type I

BackgroundMyotonic Dystrophy type I (DM1) is the most common muscular dystrophy in adults. Previous reports have highlighted that neuromuscular junctions (NMJs) deteriorate in skeletal muscle from DM1 patients and mouse models thereof. However, the underlying pathomechanisms and their contribution to muscle dysfunction remain unknown.MethodsWe compared changes in NMJs and activity-dependent signalling pathways in HSALR and Mbnl1ΔE3/ΔE3 mice, two established mouse models of DM1.ResultsMuscle from DM1 mouse models showed major deregulation of calcium/calmodulin-dependent protein kinases II (CaMKIIs), which are key activity sensors regulating synaptic gene expression and acetylcholine receptor (AChR) recycling at the NMJ. Both mouse models exhibited increased fragmentation of the endplate, which preceded muscle degeneration. Endplate fragmentation was not accompanied by changes in AChR turnover at the NMJ. However, the expression of synaptic genes was up-regulated in mutant innervated muscle, together with an abnormal accumulation of histone deacetylase 4 (HDAC4), a known target of CaMKII. Interestingly, denervation-induced increase in synaptic gene expression and AChR turnover was hampered in DM1 muscle. Importantly, CaMKIIβ/βM overexpression normalized endplate fragmentation and synaptic gene expression in innervated Mbnl1ΔE3/ΔE3 muscle, but it did not restore denervation-induced synaptic gene up-regulation.ConclusionsOur results indicate that CaMKIIβ-dependent and -independent mechanisms perturb synaptic gene regulation and muscle response to denervation in DM1 mouse models. Changes in these signalling pathways may contribute to NMJ destabilization and muscle dysfunction in DM1 patients.

A genome-wide association study identifies a locus associated with knee extension strength in older Japanese individuals

Sarcopenia is a common skeletal muscle disease in older people. Lower limb muscle strength is a good predictive value for sarcopenia; however, little is known about its genetic components. Here, we conducted a genome-wide association study (GWAS) for knee extension strength in a total of 3452 Japanese aged 60 years or older from two independent cohorts. We identified a significant locus, rs10749438 which is an intronic variant in TACC2 (transforming acidic coiled-coil-containing 2) (P = 4.2 × 10−8). TACC2, encoding a cytoskeleton-related protein, is highly expressed in skeletal muscle, and is reported as a target of myotonic dystrophy 1-associated splicing alterations. These suggest that changes in TACC2 expression are associated with variations in muscle strength in older people. The association was consistently observed in young and middle-aged subjects. Our findings would shed light on genetic components of lower limb muscle strength and indicate TACC2 as a potential therapeutic target for sarcopenia.

Therapeutic potential of oleic acid supplementation in myotonic dystrophy muscle cell models

BackgroundWe recently reported that upregulation of Musashi 2 (MSI2) protein in the rare neuromuscular disease myotonic dystrophy type 1 contributes to the hyperactivation of the muscle catabolic processes autophagy and UPS through a reduction in miR-7 levels. Because oleic acid (OA) is a known allosteric regulator of MSI2 activity in the biogenesis of miR-7, here we sought to evaluate endogenous levels of this fatty acid and its therapeutic potential in rescuing cell differentiation phenotypes in vitro. In this work, four muscle cell lines derived from DM1 patients were treated with OA for 24 h, and autophagy and muscle differentiation parameters were analyzed.ResultsWe demonstrate a reduction of OA levels in different cell models of the disease. OA supplementation rescued disease-related phenotypes such as fusion index, myotube diameter, and repressed autophagy. This involved inhibiting MSI2 regulation of direct molecular target miR-7 since OA isoschizomer, elaidic acid (EA) could not cause the same rescues. Reduction of OA levels seems to stem from impaired biogenesis since levels of the enzyme stearoyl-CoA desaturase 1 (SCD1), responsible for converting stearic acid to oleic acid, are decreased in DM1 and correlate with OA amounts.ConclusionsFor the first time in DM1, we describe a fatty acid metabolism impairment that originated, at least in part, from a decrease in SCD1. Because OA allosterically inhibits MSI2 binding to molecular targets, reduced OA levels synergize with the overexpression of MSI2 and contribute to the MSI2 > miR-7 > autophagy axis that we proposed to explain the muscle atrophy phenotype.